Martin E. Evans

Polymyxin B Sulfate and Colistin: Old Antibiotics for Emerging Multiresistant Gram-Negative Bacteria

BACKGROUND: Polymyxin B sulfate and colistin, also known as colistimethate, have not been used for many years because less toxic antimicrobials are available. Gram-negative bacteria that are resistant to the aminoglycosides, β-lactams, and fluoroquinolones are becoming more common. These bacteria are often susceptible to the polymyxins. OBJECTIVE: To present a review of the chemistry, antibacterial spectrum, dosing, pharmacokinetics, toxicity, and indications for polymyxin B sulfate and colistin. DATA SOURCE: A MEDLINE search (1966–1998) of the English-language literature was performed to identify primary literature on the polymyxins. Older citations (1949–1965) were identified through the bibliographies of these articles. STUDY SELECTION: All available reports of in vitro antibacterial activity, animal and clinical trials, and case reports were reviewed. DATA SYNTHESIS: The polymyxins are amphipathic molecules that interact with lipopolysaccharide in the bacterial outer membrane. They have potent antiendotoxic properties and antibacterial activity against Pseudomonas aeruginosa and many of the Enterobacteriaceae. Polymyxin B and colistin are usually given at a dose of 1.5–2.5 and 5 mg/kg/d, respectively, in two divided doses. Dosing must be altered in renal failure since the kidney is the primary route of elimination. Distribution into pleural fluid, joints, and cerebrospinal fluid is poor. Toxic effects involve the kidney and central nervous system. The polymyxins are recommended for serious systemic infections caused by gram-negative bacteria that are resistant to other agents. CONCLUSIONS: Polymyxin B sulfate and colistin have a role in the therapy of multidrug-resistant gram-negative bacterial infections.

Tularemia: a 30-year experience with 88 cases.

Drawing upon our experience with 88 cases and a survey of the English literature, we reviewed the clinical, pathophysiological, and epidemiological aspects of tularemia. Tularemia can be thought of as two syndromes--ulceroglandular and typhoidal. This dichotomy simplifies earlier nomenclature and emphasizes the obscure typhoidal presentation. Clinical manifestations suggest that the two syndromes reflect differences in host response. In ulceroglandular tularemia the pathogen appears to be well contained by a vigorous inflammatory reaction. Pneumonia is less common and the patients prognosis is good. In typhoidal disease there are few localizing signs; pneumonia is more common; and the mortality without therapy is much higher, suggesting that the host response is somehow deficient. Francisella tularensis is an extremely virulent pathogen capable of initiating infection with as few as 10 organisms inoculated subcutaneously. During an incubation period of 3 to 6 days the host responds first with polymorphonuclear leukocytes and then macrophages. Granulocytes are unable to kill the pathogen without opsonizing antibody leaving cellular immunity to play the major role in host defense. One to 2 weeks after infection, a vigorous T-lymphocyte response can be detected in vitro with lymphocyte blast transformation assays and in vivo with an intradermal skin test, which, unfortunately, is not commercially available. Humoral immunity, often used as a diagnostic modality, appears 2 to 3 weeks into the illness. Cellular immunity is long-lasting, accounting for the common reoccurrence of localized disease upon repeated exposures to the pathogen. There are no symptoms that distinguish the ulceroglandular from the typhoidal syndrome. A pulse-temperature dissociation is seen in less than half of the patients. The location of ulcers and enlarged lymph nodes give a clue to the likely vector since lesions located on the upper extremities are more commonly associated with mammalian, and those of the head and neck and lower extremities with arthropod, vectors. Pharyngitis, pericarditis, and pneumonia can complicate both syndromes, although the latter is much more common in typhoidal disease. Hepatitis, usually of a mild degree, is common and occasionally erythema nodosum is seen. No specific laboratory tests characterize tularemia, and cultures of the pathogen are often difficult to obtain because of the special growth requirements of Francisella tularesis and the inability of many clinical laboratories to handle the dangerous pathogen.(ABSTRACT TRUNCATED AT 400 WORDS)

Levofloxacin Failure in a Patient with Pneumococcal Pneumonia

OBJECTIVE: To report a case of levofloxacin failure in a patient with a penicillin-sensitive Streptococcus pneumoniae pneumonia. CASE SUMMARY: A previously healthy, immunocompetent, 53-year-old white man presented with penicillin-sensitive S. pneumoniae pneumonia. The patient was empirically placed on levofloxacin monotherapy, which was continued due to a local penicillin shortage. When the patient failed to improve, further susceptibility testing was ordered. The organism was found to have a penicillin minimum inhibitory concentration (MIC) of 0.023 μg/mL and a levofloxacin MIC of 6 μg/mL. Effective antimicrobial therapy was delayed, as clinicians did not anticipate fluoroquinolone resistance. DISCUSSION: Newer fluoroquinolones such as levofloxacin have good activity against most S. pneumoniae isolates and are used for the treatment of pneumonia. Although resistance to these agents is rare, it has been reported. Current guidelines from the National Committee for Clinical Laboratory Standards do not recommend initial fluoroquinolone susceptibility testing. CONCLUSIONS: As fluoroquinolone resistance may not be identified by susceptibility patterns to other antibiotics, early fluoroquinolone susceptibility testing and increased awareness of resistance may aid clinicians in their treatment of pneumococcal disease.

Trimethoprim‐Sulfamethoxazole as a Viable Treatment Option for Infections Caused by Methicillin‐Resistant Staphylococcus aureus

Objective. To review available data regarding the efficacy of trimethoprim‐sulfamethoxazole (TMP‐SMX) for the treatment of infections caused by methicillin‐resistant Staphylococcus aureus (MRSA).

Vancomycin Use in a University Medical Center: Comparison With Hospital Infection Control Practices Advisory Committee Guidelines

OBJECTIVE To compare actual vancomycin use in a hospital with the guidelines proposed by the Hospital Infection Control Practices Advisory Committee (HICPAC) of the Centers for Disease Control and Prevention. DESIGN One-month prospective survey of all patients given vancomycin. Data were collected from patient and laboratory records and discussions with prescribing physicians. SETTING Four hundred sixty-one-bed tertiary-care university hospital. RESULTS Only 35% of the 101 vancomycin orders written during the audit were consistent with HICPAC guidelines. Twenty-eight patients were begun on vancomycin for the treatment of documented infections due to beta-lactam-resistant gram-positive bacteria or because preliminary culture results suggested such bacteria were present. Seven methicillin-resistant Staphylococcus aureus, two ampicillin-resistant enterococci, and 10 coagulase-negative staphylococci were recovered. Vancomycin use was judged inappropriate in 66 patients. The drug was used empirically without obtaining appropriate cultures (44 patients), as surgical prophylaxis (6 patients), for primary treatment of antibiotic-associated colitis (3 patients), for convenience in a hemodialysis patient (1 patient), or for other reasons not recommended by HICPAC (12 patients). CONCLUSIONS Vancomycin use in our teaching center often was inconsistent with HICPAC guidelines. Information from the audit will be useful for designing strategies to improve vancomycin use.

Influenza control in acute care hospitals

BACKGROUND Influenza causes increased morbidity and mortality among patients in longterm care facilities, but little information is available on the impact of influenza in acute care settings. We wished to have such information when revising our hospital influenza control policy. METHODS We reviewed recent reports of influenza among patients in acute care hospitals and surveyed large (approximately 500-bed) acute care teaching hospitals by telephone to determine the nature of their influenza control policies. RESULTS Seventeen reports of influenza outbreaks in acute care hospitals were published from 1959 to 1994. Influenza A caused 13 of these outbreaks. Five involved children and 12 involved adults. The mean number of patients in each outbreak was 14 (range 1 to 49), with a mortality rate of 0% to 50% (median 0%, mean 6.5%). Health care workers were implicated in transmission in five reports. Vaccine was used infrequently during the outbreaks, and use of chemoprophylaxis was not reported. Our survey of current practices in 15 university-affiliated hospitals from 12 states revealed that all offered vaccine in the fall but none required either immunoprophylaxis or chemoprophylaxis at any time. Only three had formal policies detailing management of influenza in the hospital. CONCLUSIONS Nosocomial influenza in acute care hospitals is infrequently reported and associated with a low mortality rate. Health care workers rarely comply with preventive measures, and few institutions have formal influenza control policies.

Pharmacodynamic Modeling of Ciprofloxacin Resistance in Staphylococcus aureus

ABSTRACT Three pharmacodynamic models of increasing complexity, designed for two subpopulations of bacteria with different susceptibilities, were developed to describe and predict the evolution of resistance to ciprofloxacin in Staphylococcus aureus by using pharmacokinetic, viable count, subpopulation, and resistance mechanism data obtained from in vitro system experiments. A two-population model with unique growth and killing rate constants for the ciprofloxacin-susceptible and -resistant subpopulations best described the initial killing and subsequent regrowth patterns observed. The model correctly described the enrichment of subpopulations with low-level resistance in the parent cultures but did not identify a relationship between the time ciprofloxacin concentrations were in the mutant selection window (the interval between the MIC and the mutant prevention concentration) and the enrichment of these subpopulations. The model confirmed the importance of resistant variants to the emergence of resistance by successfully predicting that resistant subpopulations would not emerge when a low-density culture, with a low probability of mutants, was exposed to a clinical dosing regimen or when a high-density culture, with a higher probability of mutants, was exposed to a transient high initial concentration designed to rapidly eradicate low-level resistant grlA mutants. The model, however, did not predict or explain the origin of variants with higher levels of resistance that appeared and became the predominant subpopulation during some experiments or the persistence of susceptible bacteria in other experiments where resistance did not emerge. Continued evaluation of the present two-population pharmacodynamic model and development of alternative models is warranted.

Evolution of Ciprofloxacin-Resistant Staphylococcus aureus in In Vitro Pharmacokinetic Environments

ABSTRACT The development of novel antibacterial agents is decreasing despite increasing resistance to presently available agents among common pathogens. Insights into relationships between pharmacodynamics and resistance may provide ways to optimize the use of existing agents. The evolution of resistance was examined in two ciprofloxacin-susceptible Staphylococcus aureus strains exposed to in vitro-simulated clinical and experimental ciprofloxacin pharmacokinetic profiles for 96 h. As the average steady-state concentration (Cavg ss) increased, the rate of killing approached a maximum, and the rate of regrowth decreased. The enrichment of subpopulations with mutations in grlA and low-level ciprofloxacin resistance also varied depending on the pharmacokinetic environment. A regimen producing values for Cavg ss slightly above the MIC selected resistant variants with grlA mutations that did not evolve to higher levels of resistance. Clinical regimens which provided values for Cavg ss intermediate to the MIC and mutant prevention concentration (MPC) resulted in the emergence of subpopulations with gyrA mutations and higher levels of resistance. A regimen producing values for Cavg ss close to the MPC selected grlA mutants, but the appearance of subpopulations with higher levels of resistance was diminished. A regimen designed to maintain ciprofloxacin concentrations entirely above the MPC appeared to eradicate low-level resistant variants in the inoculum and prevent the emergence of higher levels of resistance. There was no relationship between the time that ciprofloxacin concentrations remained between the MIC and the MPC and the degree of resistance or the presence or type of ciprofloxacin-resistance mutations that appeared in grlA or gyrA. Regimens designed to eradicate low-level resistant variants in S. aureus populations may prevent the emergence of higher levels of fluoroquinolone resistance.

Use of Macrolides and Tetracyclines for Chronic Inflammatory Diseases

OBJECTIVE: To review the efficacy of macrolides and tetracyclines in several chronic inflammatory conditions. DATA SOURCES: Searches of MEDLINE (1966–March 2004) and an extensive bibliography search were undertaken. Key terms included acne, blepharitis, cardiovascular disease, cystic fibrosis, periodontitis, rosacea, and rheumatoid arthritis. STUDY SELECTION AND DATA EXTRACTION: Data were obtained primarily from randomized placebo-controlled trials upon which key recommendations are based. DATA SYNTHESIS: Antibiotics are often prescribed for months or even years for treatment of chronic inflammatory conditions such as acne, blepharitis, cardiovascular disease, cystic fibrosis, periodontitis, rosacea, and rheumatoid arthritis. Randomized controlled trials have shown that azithromycin is useful in the management of cystic fibrosis and the tetracyclines are beneficial in the management of rheumatoid arthritis, acne, blepharitis, and periodontitis. Several large, randomized controlled trials have failed to show any benefit of macrolides in the secondary prevention of cardiovascular disease. No randomized placebo-controlled clinical trials have been performed to assess the efficacy of macrolides or tetracyclines in patients with rosacea. CONCLUSIONS: The use of tetracyclines and macrolides for rosacea is based primarily on anecdotal reports or open-label trials. Limited clinical trials support the use of tetracyclines or macrolides in acne, blepharitis, periodontitis, rheumatoid arthritis, and cystic fibrosis. Trials to date do not support the use of antibiotics for secondary prevention of cardiovascular disease.

The Effect of an Antimicrobial Formulary Change on Hospital Resistance Patterns

A university hospital formulary change that was designed to reduce the use of the third‐generation cephalosporins ceftazidime and cefotaxime and replace them with the so‐called “fourth‐generation” cephalosporin cefepime was evaluated. A retrospective review of antibiotic use and antimicrobial resistance during two 6‐month periods before and after the formulary change was performed. All hospital patients with vancomycin‐resistant Enterococcus (VRE), ceftazidime‐resistant Klebsiella pneumoniae (CRKP), methicillin‐resistant Staphylococcus aureus (MRSA), piperacillin‐resistant Pseudomonas aeruginosa (PRPA), and ceftazidime‐resistant P. aeruginosa (CRPA) infections were included in the study. Ceftazidime use decreased from 9600 g to 99 g, and cefotaxime use decreased from 6314 g to 732 g, which represented a combined decrease of 89%. Use of cefepime increased from 0 g to 5396 g. Infections from CRKP decreased from 13% to 3%, PRPA infections decreased from 22% to 14%, and CRPA infections decreased from 25% to 15% (p<0.05 for all). Infections from MRSA dropped insignificantly, and VRE infections increased significantly. Substituting cefepime for ceftazidime and cefotaxime while reducing the overall use of cephalosporins appears to decrease rates of CRKP, PRPA, and CRPA.